Bradykinin is a nonapeptide having the amino acid sequence EQU Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg
hereinafter referred to as SEQ ID NO:1, belonging to a family of kinins that also includes kallidin or lysyl-bradykinin which has the amino acid sequence EQU Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg
hereinafter referred to as SEQ ID NO:2, and methionyl-lysyl-bradykinin, which has the amino acid sequence EQU Met-Lys-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg
hereinafter referred to as SEQ ID NO:3. These kinins are released from plasma precursors (kininogens) by the action of plasma and tissue kallikreins to regulate the essential physiological functions. For a review of the therapeutic prospects of bradykinin receptor antagonists, see, J. N. Sharma, General Pharmacology 24:267-274 (1993).!
Bradykinin mediates pain, vascular permeability, inflammation, gastrointestinal function, and smooth muscle tone in vascular and other tissues. Bradykinin is one of the key mediators of the body's response to trauma and injury. Abnormally raised bradykinin release in response to noxious agents, tissue injury or lack of circulating kininases can induce several pathological conditions ranging from rheumatoid arthritis to asthma.
Receptors for bradykinin exist in the nervous system, epithelia, smooth muscle, and fibroblasts. In each tissue type bradykinin triggers specific responses including neurotransmitter release, muscle contraction, fluid secretion by epithelia, and stimulation of cell growth. The initial interaction for the biological response occurs at a bradykinin receptor site on a cell.
Bradykinin can activate neurons and produce neurotransmitter release. It can activate phospholipases C and A.sub.2 resulting in the production of a number of bioactive intermediates.
Bradykinin receptors are G protein-coupled receptors that activate phospholipase C or phospholipase A.sub.2 and increase the synthesis of inositol triphosphate, diacylglycerol, and arachidonic acid. Olsen, et al., Journal of Bioloical Chemistry, 263:18030-18035 (1988). G proteins are a family of membrane proteins that become activated only after binding guanosine triphosphate. Activated G proteins in turn activate an amplifier enzyme on the inner face of a membrane; the enzyme then converts precursor molecules into second messengers.
Bradykinin receptors have been classified as B1 and B.sub.2 on the basis of the relative potencies of agonists (kinins) and antagonists (kinin analogues) on various pharmacological preparations. R. J. Vavrek and J. M. Stewart, Peptides, 6:161-164 (1985). B.sub.1 receptors are generated de novo in the vascular smooth muscle during incubation of isolated tissue and during antigen-induced arthritis. J. Bouthiller, et al., British Journal of Pharmacology, 92:257-264 (1987).
There continues to exist a need for non-peptidyl bradykinin receptor antagonists. Pharmacological agents containing guanidine moieties are known. See, e.g., U.S. Pat. Nos. 5,059,624 and 5,028,613. These two issued patents describe a series of pyrroloquinoline alkaloids isolated and purified from certain marine sponges. U.S. Pat. No. 5,288,725, issued Feb. 22, 1994, describes a series of pyrroloquinoline guanidine compounds useful as bradykinin receptor antagonists. U.S. Pat. No. 5,212,182, issued May 18, 1993, describes a series of quinolinyl- and naphthalenylbenzamides and benzylamines which are useful as bradykinin receptor antagonists possessing analgesic properties. U.S. Pat. No. 5,216,165, issued Jun. 1, 1993, describes a series of N-substituted aminoquinolines useful as analgesic agents by means of their properties as bradykinin receptor antagonists.
There continues to exist a need for efficacious and safe compounds which are useful as bradykinin receptor antagonists. The current invention provides a novel series of such antagonists which are administrable by a variety of routes, including orally as well as parenterally.